Autosomal dominant cerbellar ataxias (ADCAs) are currently classified into three groups based on the symptoms presented: ADCA I, ADCA II, and ADCA III. All ADCAs exhibit a degree of cerbellar dysfunction. ADCA I is based on the presence of pyramidal and extra pyramidal symptoms, ophthalmoplegia or a combination thereof. ADCA II is based on the presence of retinopathy. ADCA III is based on the absence of the ADCA I and II symptoms (Zu et al., 1999). A number of SCA genes have been identified or mapped and designated by the HUGO nomenclature committee “spinocerebellar ataxia type n (SCAn)” where “n” refers to the numeric number in order of mapping; these genes include SCA1, SCA2, SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, SCA11, SCA12, SCA13, SCA14, SCA15, SCA16 and SCA17. Additionally, two ADCA gene designated MJD (also known as SCA3) and DRPLA have been identified for Machado-Joseph disease and dentatorubral pallidolysian atrophy, respectively.(Silveira et al., 2000). Many of the SCA types are due to a mutation in one of the genes that involves a trinucleotide-rep eat expansion in the gene (Zu et al., 1999). The number of repeats often correlates with the age of onset and the severity of the symptoms (O'Sullivan Smith et al., 1999). Diseases other than ADCAs have also been shown to have an expanded trinucleotide repeat as the mutation. Suppression of transcription by a large intronic repeat expansion in Friedreich's ataxia where an expanded GAA repeat interferes with transcription of the FRDA gene has been documented (Bidichandani et al., 1998). Fragile X syndrome and FRAXE mental retardation are caused by CGG and CCG repeat expansion in the 5′ untranslated region of the FMR1 and FMR2 gene, respectively. In DM1, an unstable CTG repeat expands up to several thousand copies in the 3′ untranslated region of the DMPK gene (Wells et al., 1998). Spinocerebellar ataxia type 10 (SCA10) is characterized by gait and limb ataxia, dysarthria, nystagmus, and occasional seizures (Zu et al., 1999; O'Sullivan Smith et al., 1999). SCA10 shows anticipation, in which the onset of the disease is earlier with each passing generation. A pedigree of Mexican-American descent that exhibits spinocerebellar ataxia type 10 has been identified (Zu et al., 1999). SCA10 is believed to be the second most common autosomal dominant cerebellar ataxia after SCA2 in Mexico.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by cerebellar ataxia and occasional seizures. Several other SCA subtypes show trinucleotide repeat expansions and prior to the present invention, it was not known whether SCA10 was due to a trinucleotide repeat expansion.
Genetic mapping studies in two families localized the SCA10 locus to chromosome 22q13-qter (Matsuura et al., 1999; Zu et al., 1999). Two recombination events narrowed the SCA10 region to a 2.7-cM region between D22S1140 and D22S1153 (Matsuura et al., 1999; Zu et al., 1999; Matsuura et al., 1999). Although the DNA sequence of the entire euchromatic part of human chromosome 22 has recently become available, there are still 11 gaps that remain to be sequenced (Dunham et al., 1999). D22S1160 and D22S1153 reside in one of these gaps. Nevertheless, two contigs composed of bacterial artificial chromosomes (BACs), phage P1-derived artificial chromosomes (PACs), and cosmids cover most of this region.
In two large families with SCA10, all patients exhibited pure cerebellar ataxia while 25% and 60% of patients in respective families had recurrent episodes of generalized motor seizures, complex partial seizures, or both (Matsuura et al., 1999; Zu et al., 1999). The clinical phenomenon, known as “anticipation,” is common in dominantly inherited SCAs, in which expanded CAG repeats coding for polyglutamine tracts in respective genes are unstable and exhibit larger expansions in successive generations (Orr et al., 1993; Pulst, et al., 1996; Sanpei et al., 1996; Imbert et al., 1996; Kawaguchi et al., 1994; David et al., 1997). Expansion of CAG repeats are involved in SCAs 1, 2, 3, 6, 7, 12, or 17 (Orr et al., 1993; Pulst, et al., 1996; Sanpei et al., 1996; Imbert et al., 1996; Kawaguchi et al., 1994; David et al., 1997; Zhuchenko et al., 1997; Holmes et al., 1999; Nakamura et al., 2001) and expansion of the CTG repeat is found at the SCA8 locus (Koob et al., 1999).
Prior to the present invention, the type of and location of the repeat responsible for spinocerebellar ataxia type 10 were unknown. The present invention provides a diagnostic test for spinocerebellar ataxia type 10.